Vaccine Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Malignant Neoplasms of Brain Clinical Trial

— ACTIVATe  

Official title:

A Complementary Trial of an Immunotherapy Vaccine Against Tumor-Specific EGFRvIII

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00643097
• Other study ID #: Pro00004040
• Secondary ID: P50NS020023CDR00
• Status: Active, not recruiting
• Phase: Phase 2
• First received: March 25, 2008
• Last updated: October 15, 2015
• Start date: September 2007
• Est. completion date: December 2016

Study information

• Verified date: October 2015
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Vaccines made from a peptide may help the body build an effective immune response to kill tumor cells. Colony-stimulating factors, such as GM-CSF, increase the number of white blood cells and platelets found in bone marrow or peripheral blood. Giving vaccine therapy after surgery may kill any tumor cells that remain after surgery.

PURPOSE: This phase II trial is studying how well vaccine therapy works in treating patients with newly diagnosed glioblastoma multiforme.

Description:

OBJECTIVES:

Primary

• To assess humoral and cellular immune responses to adjuvant PEP-3-KLH conjugate vaccine in patients with newly diagnosed glioblastoma multiforme (GBM).

• To assess the clinical efficacy of the PEP-3-KLH conjugate vaccine, in terms of progression-free survival, in patients with newly diagnosed GBM.

Secondary

• To determine whether patients with GBM, who are known to be at least mildly immunosuppressed, can respond to standard and proven vaccine strategies.

• To assess for any potential toxicity to the PEP-3-KLH conjugate vaccine in patients with newly diagnosed GBM.

OUTLINE: This is a multicenter study. Patients are stratified according to participating center.

At the time the study was initiated, standard of care temozolomide was not established, therefore, Arm I (ACTIVATE)was given without monthly cycles of temozolomide. At the point of interim analysis, monthly cycles of temozolomide had become standard of care. Arm II was then given the standard of care 5-day cycles of monthly temozolomide and during this time, dose-intensified temozolomide was in trials to compare with the 5-day temozolomide. Therefore, Arm III was initiated to determine the immunologic effects of 21-day monthly cycles of temozolomide with vaccine.

• Arm I (ACTIVATE): Patients receive PEP-3-KLH conjugate vaccine and sargramostim (GM-CSF) intradermally on days 1, 15, and 29 and then monthly in the absence of disease progression or unacceptable toxicity.

• Arm II (ACT II Standard (STD)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 200 mg/m2 for the first 5 days of a 28 day cycle.

• Arm III (ACT II Dose-intensified (DI)): Patients first receive 3 initial vaccinations of an epidermal growth factor receptor variant III (EGRRvIII)- specific peptide (PEP-3) keyhole limpet hemocyanin (KLH) conjugate vaccine and sargramostim (GM-CSF) biweekly starting within 6 weeks of completing radiation. Additional vaccinations are given until clinical or radiographic evidence of progression or death. Patients subsequently receive temozolomide at a targeted dose of 100 mg/m2 for the first 21 days of a 28 day cycle.

• Patients undergo delayed-type hypersensitivity (DTH) skin testing* at baseline, after the third vaccination, and then monthly thereafter. Patients also undergo leukapheresis to obtain sufficient peripheral blood lymphocytes for immunologic monitoring at baseline, after the third vaccination, and then, if applicable, at the time of positive DTH response, disease progression, or after the sixth course of post-radiotherapy temozolomide. Methods used for immunologic monitoring include Enzyme-linked Immunospot(ELISPOT) assays, cytotoxicity assays, fluorescence activated cell sorting (FACS), and ELISA.

NOTE: *Patients with positive DTH skin testing, also undergo skin punch biopsies.

After completion of study therapy, patients are followed periodically.

Other known NCT identifiers

• NCT00090597

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 40
• Est. completion date: December 2016
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed newly diagnosed glioblastoma multiforme

• Has undergone prior gross total resection (GTR) followed by conformal radiotherapy* with or without concurrent chemotherapy

• GTR is defined as = 95% volumetric resection of the contrast-enhancing component on the preoperative MRI

• Residual radiographic contrast enhancement on post-resection CT scan or MRI must be = 1 cm in maximal diameter in any two perpendicular axial planes

• No evidence of disease progression after completion of radiotherapy* NOTE:

*Patients may enroll in part 2 of the study within 2 weeks after surgery; these patients will receive radiotherapy with concurrent chemotherapy during the study

• EGFRvIII-positive tumor by immunohistochemistry, polymerase chain reaction, or related molecular techniques

• Karnofsky performance status 80-100%

• Curran group status I-IV

• Signed informed consent form

Exclusion Criteria:

• Absolute Neutrophil Count (ANC) < 1,000/mm³

• Platelet count < 50,000/mm³

• Prothrombin Time/Partial Thromboplastin Time (PT/PTT) > 1.5 times normal

• Positive hepatitis B (HB) surface antigen (HbsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc)

• Pregnant or nursing

• Positive pregnancy test

• Active infection requiring treatment

• Unexplained febrile illness (T max > 101.5 F)

• Inflammatory bowel disease, lupus erythematosus, rheumatoid arthritis, or other autoimmune disease

• Known immunosuppressive disease

• Known HIV infection

• Diffuse leptomeningeal disease

• Unstable or severe concurrent medical condition, such as severe heart and lung disease or active hepatitis

• Demonstrated allergy to temozolomide or inability to tolerate temozolomide for reasons other than lymphopenia

• Concurrent corticosteroids (except for nasal or inhaled steroids) at a dose above physiologic levels (> 2 mg of dexamethasone/day).

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Neoplasms
• Malignant Neoplasms of Brain
• Neoplasms

Intervention

Biological:
• PEP-3 vaccine
Given intradermally
• sargramostim
Given intradermally

Drug:
• Temozolomide
Standard of care chemotherapy

Locations

Country	Name	City	State
United States	Duke University Medical Center	Durham	North Carolina
United States	M. D. Anderson Cancer Center at University of Texas	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
John Sampson	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, Friedman AH, Friedman HS, Gilbert MR, Herndon JE, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling R, Shi W, Vredenburgh JJ, Bigner DD, Heimberger AB. Greater chemotherapy-induced lymphope — View Citation

Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, Gilbert MR, Herndon JE 2nd, McLendon RE, Mitchell DA, Reardon DA, Sawaya R, Schmittling RJ, Shi W, Vredenburgh JJ, Bigner DD. Immunologic escape after prolonged progression-free su — View Citation

Schmittling RJ, Archer GE, Mitchell DA, Heimberger A, Pegram C, Herndon JE 2nd, Friedman HS, Bigner DD, Sampson JH. Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods. 2008 Nov 30;339(1):74-81. d — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Humoral and Cellular Immune Response	Number of patients that developed a delayed-type hypersensitivity (DTH) response at following vaccination. Any skin reaction in response to the intradermal injection of the antigen was measured and recorded. A positive skin test was defined as > 5 mm induration (swelling).	26 months	No
Primary	Clinical Efficacy of Vaccination, in Terms of Progression-free Survival (PFS)	Time in months from the start of study treatment to the date of first progression according to Macdonald criteria, or to death due to any cause. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.; Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).	58 months	No
Secondary	Response to Vaccination	The objective is to assess the duration of immunosuppressive cytokine secretion and to identify a receptive interval for active immunotherapy. Immunosuppression will determined by monitoring a panel of immunosuppressive serum/plasma cytokines longitudinally and by determining the response of each patient to Recombivax Hepatitis B (HB) vaccination. Response is defined as seropositive or seronegative to the Hepatitis B surface antigen.	26 months	No
Secondary	Toxicity to PEP-3 Vaccine Immunization	To assess for any potential toxicity to the PEP-3 vaccine immunization in patients with newly diagnosed glioblastoma, Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was used to tabulate any toxicities attributable to PEP-3. The number of patients with toxicity attributable to vaccine while on study are tabulated.	26 months	Yes